1. Field of the Invention
The present invention relates to a novel methylhydroxylaminopropanol derivative and its use as an intermediate for preparation of 3-methylamino-1-(2-thienyl)propan-1-ol.
2. Description of Related Art
3-methylamino-1-(2-thienyl)propan-1-ol has been shown to be an important intermediate for preparation of (+)-(S)—N-methyl-3-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine oxalate (Duloxetine®), an antidepressant drug. Various methods have been proposed to prepare 3-methylamino-1-(2-thienyl)propan-1-ol. For example, Chirality, 12, 26 (2000) discloses a process as shown in the following scheme:

In this example, thiophene is used as the starting material to be acylated by Friedel-Crafts reaction so as to form 3-chloro-1-(2-thienyl)-propanone, then 3-chloro-1-(2-thienyl)-propanone is reduced to 3-chloro-1-(2-thienyl)-propan-1-ol, and 3-chloro-1-(2-thienyl)-propan-1-ol is aminated to form 3-methylamino-1-(2-thienyl)-propan-1-ol with methylamine. In this process, large excess (20 equivalents) of methylamine is required for the amination reaction and the overall yield is low (24%), which renders this process economically less competitive.
U.S. Pat. No. 7,259,264 discloses another process for preparing 3-methylamino-1-(2-thienyl)propan-1-ol as shown in the following scheme:

In accordance with U.S. Pat. No. 7,259,264, 3-methylamino-1-(2-thienyl)-propan-1-ol is prepared by reducing an intermediate, 3-methylamino-1-(2-thienyl)-1-propanone (compound V). 2-acetylthiophene is used as the starting material for preparation of 3-methylamino-1-(2-thienyl)-1-propanone (compound V) through diketone (compound III) route or dimethylaminoketone (compound IV) route, and then 3-methylamino-1-(2-thienyl)-1-propanone is reduced to 3-methylamino-1-(2-thienyl)-propan-1-ol. When the above preparation is performed through diketone (compound III) route, large excess (20 equivalents) of methylamine is required, which leads to involvement of complex unit operation of methylamine recycling. Alternatively, when the above preparation is performed through dimethylaminoketone (compound IV) route, large excess (20 equivalents) of methylamine is also required to carry out the amine exchange reaction and the yield is not very high (about 60%). Therefore, the extensive work of purification is required for both routes to prepare 3-methylamino-1-(2-thienyl)-1-propanone (compound V), which leads to higher cost for preparation of 3-methylamino-1-(2-thienyl)propan-1-ol.
Thus, there is a demand for a simple and more efficient process for preparing 3-methylamino-1-(2-thienyl)propan-1-ol with higher yield and lower cost.